Weight disorders such as obesity affect a widespread portion of society. Over 300,000 deaths are annually attributed to weight disorders and weight-related conditions. While the underlying causes of such disorders remain unclear, many different weight loss methods and drugs have been proposed. These approaches tend to fall into one of four categories. The first category involves controlling the energy intake of the individual. This is most typically achieved through modification of appetite. This category also includes surgical procedures such as gastric partitioning, jejunoileal bypass, vagotomy, and jaw wiring, as well as pharmaceuticals for inhibiting fat digestion. Also included are behavioral approaches such as low calorie food selection. The second category involves controlling an individual's energy expenditure, or thermogenesis. Typically this is accomplished through exercise, or by administration of thermogenic agents. The third category involves regulating certain hormonal and other metabolic factors that control the amount of energy substrates that become available to cells and tissues. The fourth category involves controlling fat reserves by regulating lipogenesis and lipolysis in adipose tissue.
In general, these methods of treating excess weight have meet with no significant long term success. A clear need therefore exists for improved method and compositions for treating or preventing excess weight.
Hypocretin is a neuropeptide originally associated with feeding. This neuropeptide is synthesized in neurons of the periformical, dorsomedial, lateral, and posterior hypothalamus (Kiyashchenko et al., J. Neurophysiol. 85(5):2008-2016 (2002), and commonly exists in one of two different forms: hypocretin-1 and hypocretin-2. The hypocretins are also referred to as orexins (orexin-1 or orexin-A; and orexin-2 or orexin-B).
Orexin has been implicated in the regulation of ingestive and other behaviors. For example, orexin has been reported to induce feeding in rats (Dube et al., Brain Res. 842(2):473477 (1999); Kotz et al., Regul. Pept. 104(1-3):27-32 (2002); Mullett et al., Neuroreport 11(1):103-108 (2000); and Sweet et al., Brain Res. 821(2):535-538 (1999)). In fact, the name orexin was given to the hypocretin peptide by a group that concluded that it stimulated appetite (Sakurai et al. Cell 92(4):573-585 (1998)). The term “orexigenic” is defined as promoting the appetite.
Orexin receptor antagonist has been reported to reduce orexin induced feeding in rats (Haynes et al., Regul. Pept. 104(1-3):153-159 (2002); and Haynes et al., Regul. Pept. 96(1-2):45-51 (2000)), prompting a recommendation that orexin receptor antagonists have potential as anti-obesity agents. Other studies report that mice deficient in hypocretin or hypocretin cells are prone to gaining weight. Thus, the role of hypocretin in nutrition is unclear.